Journal of Pharmacy and Pharmacology 4 (2016) 686-691 doi: 10.17265/2328-2150/2016.12.005

RMC (Renal Medullary Cancer): A Case Report and

Literature Review

Patrícia Taranto1, Rodrigo Coutinho Mariano1, Daniel Eiger1, Gustavo Schvartsman2, Samy Tarnovschi1, Renee

Zon Filippi1 and Andrey Soares1

1. Hospital Israelita Albert Einstein (HIAE), São Paulo (SP) 05651901, Brazil

2. University of Texas MD Anderson Cancer Center (MDACC), Houston 77030, Texas, USA

Abstract: RMC (renal medullary carcinoma) is considered a rare entity, corresponding to approximately 2% of primary kidney tumors, usually occurring in the second decade of the patient’s life and it is closely related with previous history of sickle cell disease. Studies have reported RMC as highly aggressive, poorly responsive to chemotherapy, surgery, radiotherapy or targeted therapy. This disease’s median overall survival is less than 12 months. We are reporting a case of a 21-year-old woman with sickle cell trait, whose initial clinical presentation was RMC already metastatic to the liver. She underwent total right nephrectomy, and her clinical picture worsened during hospitalization with pneumonia, bowel obstruction, oliguria and death in less than two months after diagnosis, with no performance status to attempt any treatment options to her cancer at any time. Although some cases in the literature had reported good response to neoadjuvant therapy, this disease has early recurrence and little response to treatment. Our objective is to call the attention for this aggressive desease to estimulate new perspectives and further studies with chemotherapy and other different kinds of treatment, mainly because only surgical intervention is an incomplete aproach.

Key words: Kidney neoplasms, RMC (renal medullary carcinoma), carcinoma, renal cell, sickle cell trait.

1. Introduction

RMC (renal medullary cancer) was first described

in 1995. It is considered a rare entity, corresponding to

approximately 2% of primary kidney tumors that

occurs primarily in young male, in the second decade

of life, particularly in patients affected by

haemoglobinopathies (especially sickle cell

anemia [1, 2]). It harbors distinct histological features,

despite sometimes being considered a subtype of

collecting duct carcinoma [3]. Case reports suggest its

extreme aggressiveness, usually presenting as

metastatic disease at diagnosis. It is poorly responsive

to chemotherapy, radiotherapy, targeted therapy and to

surgery, with a median overall survival of less than

12 months [4]. Rathmell and Monk [5] described a

case series in which the use of ddMVAC (dose dense

methotrexate, vinblastine, doxorubicin and cisplatin)

Corresponding author: Patrícia Taranto, research fellow,

research field: oncology.

in three patients produced a significant benefit in

symptom palliation and survival [5]. Another series

performed karyotyping evaluation of four patients,

showing all had chromosome 11 monosomy and two

of them had chromosome 3 abnormalities [6].

This is a case report of a 21-year-old female patient

with sickle cell trait and family members with sickle

cell disease, who presented with de novo metastatic

RMC to the liver. She was submitted to a total right

nephrectomy but unfortunately developed clinical

deterioration due to a pneumonia and bowel

obstruction, ultimately leading to oliguria and death in

less than two months, without active treatment to the

cancer.

2. Case Report

This is a 21-year-old female patient with sickle cell

trait and family members with sickle cell anemia, who

presented with weight loss (28 pounds in six months),

right flank pain and an abdominal mass on physical

D DAVID PUBLISHING

RMC (Renal Medullary Cancer): A Case Report and Literature Review

687

Fig. 1 Abdominal MRI showing an expansive right kidney lesion.

exam. MRI (magnetic resonance imaging) of the

abdomen showed a 7.6 cm mass in the right kidney,

associated with nodules of up to 1.4 cm in the perirenal

space suggestive of implants, and extensive

heterogeneous nodal enlargement of up to 4 cm in the

right retrocural chain and adjacent to the inferior vena

cava (Fig. 1). Furthermore, the liver was enlarged with

sparse focal lesions of up to 2 cm.

The patient was submitted to a total right

nephrectomy, but in the post-operative setting

developed a nosocomial pneumonia with pleural

effusion, requiring broad-spectrum antibiotics and

multiple pleural drainages in the ICU (intensive care

unit). Right pleurodesis was performed and pleural

effusion cytology was negative for neoplastic cells. She

developed abdominal distension followed by nausea

and vomiting, compatible with intestinal subocclusion,

with no improvement with clinical management. Due

to hemodynamic instability, surgery was not feasible.

She rapidly progressed with worsening of renal

function and died less than two months after diagnosis.

3. Pathological Findings

The surgical specimen consisted of a neoplasia

measuring 7 cm in its largest axis, with ill-defined

borders, infiltration of the renal pelvis, fat in the renal

sinus and its surrounding fat tissue (Fig. 2).

Noncontiguous invasion to the ipsilateral adrenal

gland and to its surrounding fat tissue was found.

Surgical margins were compromised.

On microscopic evaluation, characteristic epithelial

cells with eosinophilic cytoplasm, large nuclei and

prominent nucleolus were seen with solid, tubular and

reticular growing features. An intense desmoplastic

reaction was showed in the stroma and a mixed

inflammatory infiltrate surrounding the neoplastic cells

was evident (Fig. 3).

By immunohistochemical staining, the neoplastic

cells were positive for PAX-8, OCT-4, EMA and

pan-cytokeratin, and had loss of the immunoreactivity

for INI-1 (Fig. 4).

Fig. 2 A picture of the macroscopic exam of the surgical specimen.

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RMC (Renal Medullary Cancer): A Case Report and Literature Review

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4. Discussion and Conclusions

Initially described by Berman [7] in 1975 as the

seventh nephropathy associated with sickle cell anemia,

RMC was interpreted as a picture of major hematuria,

papillae necrosis, nephrotic syndrome, renal infarction,

hipoestenuria and pyelonephritis [7]. Davis et al. [8]

reported in 1995 a series of 34 cases of an aggressive

neoplasia with peculiar microscopic features probably

originating in the collecting ducts of the kidneys in

young patients with sickle cell anemia, therefore

describing this new disease, “medullary carcinoma of

the kidney”, as the seventh sickle cell anemia

nephropathy [8].

This neoplasm occurs mostly in young black males,

especially in those with sickle cell trait (instead of the

anemia per se) [9]. It is usually incidentally detected,

with clinical features resembling those of classic

kidney carcinoma, such as flank pain, palpable mass,

frank hematuria, weight loss and a predilection for the

right side. The majority of patients present with de

novo metastatic disease, especially to regional lymph

nodes, adrenal glands, lungs, liver, inferior vena cava

e peritoneum [10], and have a very aggressive disease

course. Commonly, it shows no response to standard

therapies, leading to a poor prognosis and median

overall survival of less than 12 months [2]. Another

series of cases from the Bronx institution reports nine

patients with RMC, being all of them with sickle cell

trait, male to female ratio of 2:1 and age at diagnosis

between 13 to 31 years. They all presented with flank

pain, two thirds presented with hematuria and one

third with a palpable mass. Eight of nine evaluated

patients had masses that varied in size between 4 cm

to 12 cm. Our patient had similar characteristics, being

21 years old at diagnosis, with the aforementioned

clinical symptoms and a 7.6 cm right kidney mass.

Despite these tumors not having any specific

radiological features, on the right clinical ground they

can be suspected on scans as an invasive mass that is

deep in the renal parenchyma, renal pelvis and

sinusoids, with kidney enlargement but without

alteration of its shape [11].

While the tumor pathogenicity is not completely

understood, it is known that there is an association

with sickle cell nephropathy and its cytogenetic

abnormalities, such as triploidy with chromosome 11

monosomy, translocation (3;8) (p21;q24) and

tetraploid with the bcr/abl translocation in the

chromosomes 9 and 22 [12-20]. Some evidences

suggest that the short arm of chromosome 11 (11p),

where the beta-globin gene is located, might be

involved in the tumor pathogenicity, too [13].

Macroscopically it is characterized as a tumor that

grows in the renal medulla with extension to the pelvis

and chalices [8]. Small satellite nodules can be found

in the normal cortex and near soft tissues.

Histologically, it is characterized by a tubulopapillary

architecture with a dark eosinophilic cytoplasm,

desmoplasia, high grade nuclear cytology, prominent

nucleolus [3], multiple hemorrhagic areas with

extensive necrosis. In the majority of cases,

lymphovascular invasion can be observed, with a

massive inflammatory infiltrate and abundant

neutrophils [1]. By immunohistochemistry analysis,

Swartzel at al. [3] reported 15 RMC specimens, where

all had positivity for the epithelial marker CAM5.5

and for epithelial membrane antigens, with absent

staining for cytokeratin 34EE12. Cytokeratins 7 and

20 and carcinoembryonic antigen had variable

expression [3]. Despite the negative result in our

patient specimen, a new histochemical marker called

INI-1 was recently described for RMC. Loss of

SMARCB1/INI-1, a tumor suppressor gene, was

initially described on rhabdoid pediatric tumors of the

central nervous system, kidney and soft tissues. More

recently, a complete loss of immunoexpression of

SMARCB/INI-1 was found in 15% of collecting duct

tumors, with no differences in clinicopathological

features or in endpoints related to the positivity of the

marker, which suits it for the differential diagnosis of

RMC [14]. Keratins AE1/AE3 and EMA are usually

RMC (Renal Medullary Cancer): A Case Report and Literature Review

690

positive, whereas for CEA the degree of positivity is

lower [15].

The available therapeutic modalities are poorly

studied, including surgery, chemotherapy,

radiotherapy and biological drugs. The majority of

patients have a low response rate and regimens are

based on the treatment of urothelial carcinomas [16].

Some authors reports treatment based on platinum

salts [17], anthracyclines [18] and Bortezomib [19].

Simpson et al. [20] reviewed RMC cases published

between 1995 and 2003 and described 28 patients

with a median overall survival of 32 weeks (range: 2

to 68 weeks), and the patients who lived the longest

were exposed to MVAC regimen.

According to the Brazilian experience, the best

responses found where with platinum-based treatments.

Molecular-targeting agents might be promising but

patients treated with sunitinib had no responses [4].

Recently, Amjad et al. [21] reported a case where a

23-year-old African American patient with sickle cell

anemia had a near complete clinical and pathological

response to ddMVAC. This particular patient had six

cycles of neoadjuvant ddMVAC with great tolerance

and no need of hospitalization, and then proceeded

with a total nephrectomy with retroperitoneal

lymphadenectomy, showing a near complete

pathological response, developing recurrence only 16

months later [21]. Another case report from Alabama

University described an 11-year-old African American

patient who was submitted to three cycles of

neoadjuvant carboplatin, gemcitabine and paclitaxel,

followed by a right nephrectomy with an aortocaval

lymphadenectomy and multiple nodule resections of

the lungs, with no evidence of diseases on the surgical

specimens of the lymph nodes and pulmonary nodules.

Six additional cycles of the same chemotherapy

treatment were delivered, with good tolerance and a

disease-free survival of 11 months. Eventually, the

patient developed headaches and focal neurological

signs, which turned out to be leptomeningeal

involvement, followed by death 24 months after the

initial diagnosis [22].

In the era of guided therapy and knowledge about

driver mutation, a case report showed a patient treated

with Everolimus (an MTOR inhibitor) maintenance

after induction chemotherapy regimen of PCG

(Paclitaxel Cisplatin-Gemcitabine) based on results of

PTEN deficiency expressed in molecular profiling and

next generation sequencing. This patient responded to

induction therapy, had complete remission and

remained in remission for seven month [23]. Other

potential new drugs to be considered are histone

deacetylase inhibitors, which have shown activity

against malignant rhabdoid tumor cell lines [24]. and

the ALK inhibitor crizotinib [25]..

Accordingly to the current epidemiology and

disease description in the literature, RMC is an

extremely rare and aggressive disease, presenting

mostly in young patients with sickle cell trait or overt

anemia. Our patient was diagnosed in her 20s, with an

expansive 7.6 cm mass in the right kidney and hepatic

metastasis. She underwent a radical nephrectomy but

unfortunately developed multiple post-op

complications and clinical deterioration, eventually

dying two months later without receiving any

systemic treatment. When facing such an aggressive

and rare clinical picture, strong suspicion and early

diagnosis are of major concern to improve this already

grim prognosis carried by these young sickle cell

patients. Despite some reports of favorable responses

to neoadjuvant therapy, the disease tends to recur

early in its course, with a paucity of effective

therapeutic options thereafter, and still remains an

unmet need for new perspectives and investigation of

chemotherapeutical interventions, since surgery itself

is an incomplete and inadequate isolated treatment

option.

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